Protein folding

Abstract

This review describes recent advances in studies on the stabilities of the three-dimensional structures of proteins and on the processes leading to the formation of these structures. The term ‘protein folding’ will be used here to denote the process of the conversion of an open polypeptide chain into the unique three-dimensional conformation of the native protein. Experimental and theoretical aspects of protein folding have been reviewed by anfinsen & Scheraga (1975). In the present article, we emphasize advances made since the writing of that review, together with a brief summary of the background of recent studies.

Conformational effects of environmentally induced, cancer-related mutations in the p53 protein.

“…12), which occurs in the extended conformational region of the 1, T energy map (12). Sequential conformations in this region of the energy map tend to be disfavored energetically in polypeptide sequences because they generally do not form favorable medium-range interresidue contacts such as exist, for example, in a-helical segments (23,24). Extended sequences in proteins are mostly stabilized by long-range interactions, such as by hydrogen bonding with other extended sequences in the protein as in pleated sheets.…”

“…It has also been used to compute the low-energy conformations of other cancerrelated proteins such as from ras, myc, fos, jun, abl, and neu (18)(19)(20)(21)(22) and from other regions of the p53 protein (23). These techniques, when applied to polypeptides, yield structures that agree well with available experimental data (15,16,24,25).…”

“…For example, in a study of 19 lung cancers from uranium miners exposed to radon, 7 patients were found to have p53 mutations, including 3 mutations in HSR A' (and 2 additional mutations immediately adjacent to HSR A' at codons 146 and 161); two of the three mutations in HSR A' were missense mutations, including one resulting in a Pro -His substitution at codon 151 (5). A study of 24 squamous cell carcinomas of the skin associated with UV exposure from sunlight and consequent C--T transitions found p53 mutations in 14 of the cases, including 2 missense mutations in HSR A' resulting in a Pro v. His substitution at codon 151 and a Pro --Ser substitution at codon 152 (6). Finally, a study of 51 non-small-cell lung cancers found 24 p53 mutations, 12 of which were attributable to G -+ T transversions characteristic of PAH exposure from cigarette smoking; 21 of the 24 were missense mutations, including 6 in HSR A', 2 of which resulted in Gly Val substitutions at codon 154 (7).…”

“…A study of 24 squamous cell carcinomas of the skin associated with UV exposure from sunlight and consequent C--T transitions found p53 mutations in 14 of the cases, including 2 missense mutations in HSR A' resulting in a Pro v. His substitution at codon 151 and a Pro --Ser substitution at codon 152 (6). Finally, a study of 51 non-small-cell lung cancers found 24 p53 mutations, 12 of which were attributable to G -+ T transversions characteristic of PAH exposure from cigarette smoking; 21 of the 24 were missense mutations, including 6 in HSR A', 2 of which resulted in Gly Val substitutions at codon 154 (7). Thus, the area around HSR A' appears to be a common site for environmentally induced mutations in p53 in certain human cancers.…”

Distance geometry and related methods for protein structure determination from NMR data

“…This question, besides of being important in the structure determination in solution by NMR data, also has some relevance for the prediction of the tertiary structure of proteins by empirical energy calculations (Nemethy & Scheraga, 1977), because the main part of the nonbonded interactions is of short-distance range compared to the radius of gyration of a typical globular protein.…”